tbuckley/cabot-search huggingface dataset:
Tucatinib promotes immune activation and synergizes with programmed cell death–1 and programmed cell death–ligand 1 inhibition in HER2-positive breast cancer
Authors: Ran Li, Sneha Sant, Emmaline Brown, Franco Caramia, Bronte Nikolic, Kylie Clarke, Ann Byrne, Luis E Lara Gonzalez, Peter Savas, Stephen J Luen, Zhi Ling Teo, Balaji Virassamy, Paul J Neeson, Phillip K Darcy, Sherene Loi
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background Programmed cell death–1 (PD-1) and programmed cell death–ligand 1 (PD-L1) inhibitors have poor efficacy in patients with trastuzumab-resistant advanced HER2-positive breast cancer. Tucatinib is a potent, selective anti-HER2 tyrosine kinase inhibitor with proven clinical benefit in the advanced setting in patients with trastuzumab resistance. We investigated if tucatinib can alter the tumor microenvironment and if this could be harnessed for therapeutic efficacy. Methods We investigated the antitumor efficacy and contribution of the immune response of tucatinib using 2 immunocompetent, HER2-positive murine breast cancer models (trastuzumab-sensitive H2N113; trastuzumab-resistant Fo5) and the efficacy of tucatinib with trastuzumab and PD-1 or PD-L1 checkpoint inhibitors. Results In both models, tucatinib statistically significantly inhibited tumor growth and demonstrated dose-dependent efficacy. Ex vivo analysis by flow cytometry of tumor-infiltrating lymphocytes in mice treated with tucatinib showed increased frequency, higher proliferation, and enhanced effector function of CD8+ effector memory T cells. Tucatinib treatment also increased frequency of CD8+PD-1+ and CD8+TIM3+ T cells, CD49+ natural killer cells, monocytes, and major histocompatibility complex II expression on dendritic cells and macrophages and a decrease in myeloid-derived suppressor cells. Gene expression analysis revealed statistically significant enrichment in pathways associated with immune activation, type I and II interferon response, adaptive immune response, and antigen receptor signaling. In vivo, tucatinib and α-PD-L1 or α-PD-1 demonstrated statistically significantly increased efficacy and improved survival of mice compared with tucatinib alone. Conclusion Tucatinib modulates the immune microenvironment favorably, and combination treatment with α-PD-L1 or α-PD-1 demonstrated increased efficacy in preclinical HER2-positive tumor models. These findings provide a rationale for investigation of tucatinib and immune checkpoint inhibition in the clinic.
DDX41 germline variants causing donor cell leukemia indicate a need for further genetic workup in the context of hematopoietic stem cell transplantation
Authors: Benjamin Rolles, Robert Meyer, Matthias Begemann, Miriam Elbracht, Edgar Jost, Matthias Stelljes, Ingo Kurth, Tim H Brümmendorf, Gerda Silling
Journal: Blood Cancer Journal (2023)
Pregnancy Outcomes in a US Cohort of Transgender People
Authors: Daphna Stroumsa, Michelle H. Moniz, Halley Crissman, Vanessa K. Dalton, Anca Tilea, Paul N. Pfeiffer, Erica E. Marsh
Journal: JAMA (2023)

This study assesses severe parental morbidity, cesarean deliveries, and preterm births among commercially and publicly insured trans people compared with cisgender people.
Feasibility and Safety of Diffusing Alpha-Emitter Radiation Therapy for Recurrent or Unresectable Skin Cancers
Authors: Mark A. D’Andrea, Noam A. VanderWalde, Matthew T. Ballo, Pradeep Patra, Gil’ad N. Cohen, Antonio L. Damato, Christopher A. Barker
Journal: JAMA Network Open (2023)

Importance Patients with recurrent or unresectable skin cancers have limited treatment options. Diffusing alpha-emitter radiation therapy (DaRT), a novel solid tumor management strategy using alpha-particle interstitial brachytherapy, may address this challenge. Objective To evaluate the feasibility and safety of using DaRT to manage recurrent or unresectable skin cancers. Design, Setting, and Participants This prospective cohort study of patients who received a 2-week to 3-week treatment course and were followed up for 24 weeks after treatment during 2021 and 2022 at 2 sites in the US. Patients with malignant skin tumors or soft tissue tumors were recruited if they had limited treatment options for tumors recurrent after prior surgery or external beam radiotherapy or unresectable tumors. Intervention Patients underwent DaRT to deliver a physical dose of 10 Gy (equivalent weighted dose of 200 CGE) to the tumor. Main Outcomes and Measures Feasibility of the DaRT procedure was evaluated based on the ability of investigators to successfully deliver radiation to the tumor. Patients were followed up for adverse events (AEs) for 24 weeks and for tumor response by physicians’ physical examination and imaging 12 weeks after device removal. Results This study included 10 participants with recurrent or unresectable skin cancer (median [IQR] age, 72 [68-75] years; 6 males [60%]; 4 females [40%]). Six patients (60%) had recurrent disease, and 4 (40%) had tumors that were deemed unresectable. Tumors were located on the nose, chin, eyelid, scalp, neck, trunk, and extremities. Median (range) tumor volume before treatment was 2.1 cm 3 (0.65-12.65 cm 3 ). The mean (SD) prescription dose coverage of the gross tumor volume was 91% (2.8%) with all tumors having coverage of 85% or more. No device-related grade 3 AEs were noted. Common AEs were grade 1 to 2 erythema, edema, and pruritus. At 12 weeks following treatment, there was a 100% complete response rate. Nine of 10 complete responses (90%) were confirmed by CT imaging. Conclusions and Relevance This cohort study suggests the feasibility and preliminary safety of DaRT in the management of recurrent or unresectable skin cancers. The favorable safety profile and high response rates are promising. A US trial for marketing approval based on this pilot study is under way. Trial Registration ClinicalTrials.gov Identifier: NCT04377360
Exposure to Secondhand Smoke and Myopia in Children Aged 6 to 8 Years in Hong Kong
Authors: Ian G. Morgan
Journal: JAMA Network Open (2023)

Youjuan Zhang, PhD; Xiu Juan Zhang, PhD; Nan Yuan, PhD; Yuzhou Zhang, PhD; Yu Meng Wang, PhD; Fangyao Tang, PhD; Mandy P. Ng, MHM; Ian C. K. Wong, PhD; Patrick Ip, MPH; Ka Wai Kam, MSc (Epidemiology); Alvin L. Young, MMedSc; Li Jia Chen, PhD; Clement C. Tham, BM, BCh; Chi Pui Pang, DPhil; Jason C. Yam, MPH
Long‐term efficacy of antipsychotic drugs in initially acutely ill adults with schizophrenia: systematic review and network meta‐analysis
Authors: Stefan Leucht, Johannes Schneider‐Thoma, Angelika Burschinski, Natalie Peter, Dongfang Wang, Shimeng Dong, Maximilian Huhn, Adriani Nikolakopoulou, Georgia Salanti, John M. Davis
Journal: World Psychiatry (2023)

Most acute phase antipsychotic drug trials in schizophrenia last only a few weeks, but patients must usually take these drugs much longer. We examined the long-term efficacy of antipsychotic drugs in acutely ill patients using network meta-analysis. We searched the Cochrane Schizophrenia Group register up to March 6, 2022 for randomized, blinded trials of at least 6-month duration on all second-generation and 18 first-generation antipsychotics. The primary outcome was change in overall symptoms of schizophrenia; secondary outcomes were all-cause discontinuation; change in positive, negative and depressive symptoms; quality of life, social functioning, weight gain, antiparkinson medication use, akathisia, serum prolactin level, QTc prolongation, and sedation. Confidence in the results was assessed by the CINeMA (Confidence in Network Meta-Analysis) framework. We included 45 studies with 11,238 participants. In terms of overall symptoms, olanzapine was on average more efficacious than ziprasidone (standardized mean difference, SMD=0.37, 95% CI: 0.26-0.49), asenapine (SMD=0.33, 95% CI: 0.21-0.45), iloperidone (SMD=0.32, 95% CI: 0.15-0.49), paliperidone (SMD=0.28, 95% CI: 0.11-0.44), haloperidol (SMD=0.27, 95% CI: 0.14-0.39), quetiapine (SMD=0.25, 95% CI: 0.12-0.38), aripiprazole (SMD=0.16, 95% CI: 0.04-0.28) and risperidone (SMD=0.12, 95% CI: 0.03-0.21). The 95% CIs for olanzapine versus aripiprazole and risperidone included the possibility of trivial effects. The differences between olanzapine and lurasidone, amisulpride, perphenazine, clozapine and zotepine were either small or uncertain. These results were robust in sensitivity analyses and in line with other efficacy outcomes and all-cause discontinuation. Concerning weight gain, the impact of olanzapine was higher than all other antipsychotics, with a mean difference ranging from -4.58 kg (95% CI: -5.33 to -3.83) compared to ziprasidone to -2.30 kg (95% CI: -3.35 to -1.25) compared to amisulpride. Our data suggest that olanzapine is more efficacious than a number of other antipsychotic drugs in the longer term, but its efficacy must be weighed against its side effect profile.
Efficacy of Endocrine Therapy Plus Trastuzumab and Pertuzumab vs De-escalated Chemotherapy in Patients with Hormone Receptor–Positive/<i>ERBB2</i>-Positive Early Breast Cancer
Authors: Oleg Gluz, Ulrike A. Nitz, Matthias Christgen, Sherko Kuemmel, Johannes Holtschmidt, Johannes Schumacher, Andreas Hartkopf, Jochem Potenberg, Kerstin Lüedtke-Heckenkamp, Marianne Just, Christian Schem, Raquel von Schumann, Cornelia Kolberg-Liedtke, Christine Zu Eulenburg, Timo Schinköthe, Monika Graeser, Rachel Wuerstlein, Ronald E. Kates, Hans Heinrich Kreipe, Nadia Harbeck
Journal: JAMA Oncology (2023)

Combination of chemotherapy with (dual) ERBB2 blockade is considered standard in hormone receptor (HR)-positive/ERBB2-positive early breast cancer (EBC). Despite some promising data on endocrine therapy (ET) combination with dual ERBB2 blockade in HR-positive/ERBB2-positive BC, to our knowledge, no prospective comparison of neoadjuvant chemotherapy vs ET plus ERBB2 blockade in particular with focus on molecular markers has yet been performed.
Coordination‐Driven Self‐Assembly of Biomedicine to Enhance Photodynamic Therapy by Inhibiting Proteasome and Bcl‐2
Authors: Rui‐Xin Wang, Rong‐Rong Zheng, Hua Cai, Ni Yang, Zu‐Xiao Chen, Lin‐Ping Zhao, Yue‐Kang Huang, Peng‐Fei Li, Hong Cheng, A‐Li Chen, Shi‐Ying Li, Lin Xu
Journal: Advanced Healthcare Materials (2023)

Tumor cells resist oxidative damage and apoptosis by activating defense mechanisms. Herein, a self-delivery biomedicine (designated as BSC) is developed by the self-assembly of Bortezomib (BTZ), Sabutoclax (Sab) and Chlorin e6 (Ce6). Interestingly, BTZ can be coordinated with Sab to promote the assembly of uniform ternary biomedicine through non-covalent intermolecular interactions. Moreover, BTZ as a proteasome inhibitor can prevent tumor cells from scavenging damaged proteins to reduce their oxidative resistance. Sab can downregulate B-cell lymphoma 2 (Bcl-2) to decrease the antiapoptotic protein. Both the proteasome and Bcl-2 inhibitions contribute to increasing cell apoptosis and amplifying photodynamic therapy (PDT) efficacy of Ce6. Encouragingly, carrier-free BSC receives all biological activities of these assembly elements, including photodynamic performance as well as inhibitory capabilities of proteasome and Bcl-2. Besides, BSC has a preferable cellular uptake ability and tumor retention property, which increase the drug delivery efficiency and bioavailability. In vitro and in vivo research demonstrate the superior PDT efficiency of BSC by proteasome and Bcl-2 inhibitions. Of special note, the coordination-driven self-assembly of BSC is pH-responsive, which can be disassembled for controlled drug release upon tumor acidic microenvironment. This study will expand the applicability of self-delivery nanomedicine with sophisticated mechanisms for tumor treatment.
<scp>V‐Set</scp> Immunoglobulin Domain–Containing Protein 4 as a Novel Serum Biomarker of Lupus Nephritis and Renal Pathology Activity
Authors: Chenling Tang, Shu Zhang, Aygun Teymur, Bowen Yang, Fariz Nazir, Qi Cai, Ramesh Saxena, Nancy J. Olsen, Chandra Mohan, Tianfu Wu
Journal: Arthritis & Rheumatology (2023)

Objective To discover novel serum biomarkers that have diagnostic or predictive value in lupus nephritis (LN). Methods Using a quantitative protein microarray, we screened for high‐abundant proteome expression in the serum of patients with LN compared to healthy controls. Top candidates from this screening were validated using a larger cohort of patients with LN compared to a disease control cohort (subjects with other chronic kidney diseases) and a healthy control cohort. Promising markers were then selected using a machine‐learning model and further validated with a larger patient cohort. The corresponding autoantibodies and immune complexes containing these proteins were also examined. Results In total, 13 proteins were found to be significantly elevated in LN patient serum in the screening, among which 8 proteins were validated by enzyme‐linked immunosorbent assay using 81 serum samples from LN patients and control subjects. Three serum markers with LN diagnostic potential were identified using feature importance analysis and further validated using 155 serum samples from LN patients and control subjects. V‐set immunoglobulin domain–containing protein 4 (VSIG4) appeared to be the most promising marker in distinguishing LN from healthy controls, with an area under the curve of 0.93. VSIG4 could also discriminate active LN from inactive LN. Furthermore, serum VSIG4 levels were positively correlated with all of the following clinical parameters: the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score (Spearman's rank correlation r s = 0.42, P &lt; 0.001), the renal domain score of the SLEDAI (r s = 0.46, P &lt; 0.001), the urinary protein‐to‐creatinine ratio (r s = 0.56, P &lt; 0.001), and the serum creatinine level (r s = 0.41, P &lt; 0.001). Importantly, we found that serum VSIG4 levels tracked with LN disease activity longitudinally, and that serum VSIG4 levels reflected the renal pathology activity index (AI), particularly the AI components of crescent formation and hyaline deposits. Conclusion VSIG4 may be a promising novel serum biomarker and therapeutic target in patients with LN. image
Antimicrobial resistance of clinical Enterobacterales isolates from urine samples, Germany, 2016 to 2021
Authors: Carolin Stoltidis-Claus, Kerstin Daniela Rosenberger, Falitsa Mandraka, Xenia Quante, Jörg Gielen, Dennis Hoffmann, Hilmar Wisplinghoff, Nathalie Jazmati
Journal: Eurosurveillance (2023)

IntroductionEmpirical therapy for the treatment of urinary tract infections should be tailored to the current distribution and susceptibility of potential pathogens to ensure optimal treatment.AimWe aimed to provide an up-to-date overview of the epidemiology and susceptibility of Enterobacterales isolated from urine in Germany.MethodsWe retrospectively analysed antimicrobial susceptibility data from 201,152 urine specimens collected between January 2016 and June 2021 from in- and outpatients. Multiple logistic regression analysis was used to evaluate the association between year of investigation and antibiotic resistance, adjusted for age, sex and species subgroup. Subgroup analyses were performed for midstream urine samples obtained from (i) female outpatients aged 15 to 50 years, (ii) female outpatients older than 50 years and (iii) male outpatients.ResultsResistance rates of less than 20% were observed for nitroxoline (3.9%), fosfomycin (4.6%), nitrofurantoin (11.7%), cefuroxime (13.5%) and ciprofloxacin (14.2%). Resistance to trimethoprim/sulfamethoxazole (SXT) (20.1%), amoxicillin-clavulanic acid (20.5%), trimethoprim (24.2%), pivmecillinam (29.9%) and ampicillin (53.7%) was considerably higher. In the subgroup of outpatient women aged 15-50 years, resistance rates were generally lower. Resistance rates of all antibiotics decreased from 2016 to 2021. Multiple logistic regression revealed the lowest adjusted odds ratio (ORadj) of 0.838 (95% confidence interval (CI): 0.819-0.858; p < 0.001) for pivmecillinam and the highest ORadj of 0.989 (95% CI: 0.972-1.007; p = 0.226) for nitrofurantoin.ConclusionsResistance has generally decreased over the past years, independent of sex, age and causative pathogen. Our data provide an important basis for empirical antibiotic recommendations in various settings and patient collectives.
Author Correction: Genetic effects on the timing of parturition and links to fetal birth weight
Authors: Pol Solé-Navais, Christopher Flatley, Valgerdur Steinthorsdottir, Marc Vaudel, Julius Juodakis, Jing Chen, Triin Laisk, Abigail L LaBella, David Westergaard, Jonas Bacelis, Ben Brumpton, Line Skotte, Maria C Borges, Øyvind Helgeland, Anubha Mahajan, Matthias Wielscher, Frederick Lin, Catherine Briggs, Carol A Wang, Gunn-Helen Moen, Robin N Beaumont, Jonathan P Bradfield, Abin Abraham, Gudmar Thorleifsson, Maiken E Gabrielsen, Sisse R Ostrowski, Dominika Modzelewska, Ellen A Nohr, Elina Hypponen, Amit Srivastava, Octavious Talbot, Catherine Allard, Scott M Williams, Ramkumar Menon, Beverley M Shields, Gardar Sveinbjornsson, Huan Xu, Mads Melbye, William Lowe, Luigi Bouchard, Emily Oken, Ole B Pedersen, Daniel F Gudbjartsson, Christian Erikstrup, Erik Sørensen, Rolv T Lie, Kari Teramo, Mikko Hallman, Thorhildur Juliusdottir, Hakon Hakonarson, Henrik Ullum, Andrew T Hattersley, Line Sletner, Mario Merialdi, Sheryl L Rifas-Shiman, Thora Steingrimsdottir, Denise Scholtens, Christine Power, Jane West, Mette Nyegaard, John A Capra, Anne H Skogholt, Per Magnus, Ole A Andreassen, Unnur Thorsteinsdottir, Struan F A Grant, Elisabeth Qvigstad, Craig E Pennell, Marie-France Hivert, Geoffrey M Hayes, Marjo-Riitta Jarvelin, Mark I McCarthy, Deborah A Lawlor, Henriette S Nielsen, Reedik Mägi, Antonis Rokas, Kristian Hveem, Kari Stefansson, Bjarke Feenstra, Pål Njolstad, Louis J Muglia, Rachel M Freathy, Stefan Johansson, Ge Zhang, Bo Jacobsson
Journal: Nature Genetics (2023)

In the abstract and "Genome-wide association analyses" section of the Results, the number of loci associated with preterm birth was shown as six instead of seven.In addition, there was a production error
Correction to Lancet Planet Health 2023; 7: e219–32
Journal: The Lancet Planetary Health (2023)

In table 3 of this Article, the association (hazard ratio) between percentage daily intake of NOVA 4 group food by mass and risk of oesophageal adenocarcinoma in model 2 should have been 1•20 (1•03-1•41).This correction has been made as of May 8, 2023.
Diet-mediated constitutive induction of novel IL-4+ ILC2 cells maintains intestinal homeostasis in mice
Authors: Wanlin Cui, Yuji Nagano, Satoru Morita, Takeshi Tanoue, Hidehiro Yamane, Keiko Ishikawa, Toshiro Sato, Masato Kubo, Shohei Hori, Tadatsugu Taniguchi, Masanori Hatakeyama, Koji Atarashi, Kenya Honda
Journal: The Journal of Experimental Medicine (2023)

Group 2 innate lymphoid cells (ILC2s) expressing IL-5 and IL-13 are localized at various mucosal tissues and play critical roles in the induction of type 2 inflammation, response to helminth infection, and tissue repair. Here, we reveal a unique ILC2 subset in the mouse intestine that constitutively expresses IL-4 together with GATA3, ST2, KLRG1, IL-17RB, and IL-5. In this subset, IL-4 expression is regulated by mechanisms similar to but distinct from those observed in T cells and is partly affected by IL-25 signaling. Although the absence of the microbiota had marginal effects, feeding mice with a vitamin B1-deficient diet compromised the number of intestinal IL-4+ ILC2s. The decrease in the number of IL-4+ ILC2s caused by the vitamin B1 deficiency was accompanied by a reduction in IL-25–producing tuft cells. Our findings reveal that dietary vitamin B1 plays a critical role in maintaining interaction between tuft cells and IL-4+ ILC2s, a previously uncharacterized immune cell population that may contribute to maintaining intestinal homeostasis.
Gluconeogenic enzyme PCK1 supports S-adenosylmethionine biosynthesis and promotes H3K9me3 modification to suppress hepatocellular carcinoma progression
Authors: Dongmei Gou, Rui Liu, Xiaoqun Shan, Haijun Deng, Chang Chen, Jin Xiang, Yi Liu, Qingzhu Gao, Zhi Li, Ailong Huang, Kai Wang, Ni Tang
Journal: Journal of Clinical Investigation (2023)

Deciphering the crosstalk between metabolic reprogramming and epigenetic regulation is a promising strategy for cancer therapy. In this study, we discovered that the gluconeogenic enzyme PCK1 fueled the generation of S-adenosylmethionine (SAM) through the serine synthesis pathway. The methyltransferase SUV39H1 catalyzed SAM, which served as a methyl donor to support H3K9me3 modification, leading to the suppression of the oncogene S100A11. Mechanistically, PCK1 deficiency-induced oncogenic activation of S100A11 was due to its interaction with AKT1, which upregulated PI3K/AKT signaling. Intriguingly, the progression of hepatocellular carcinoma (HCC) driven by PCK1 deficiency was suppressed by SAM supplement or S100A11 knockout in vivo and in vitro. These findings reveal the availability of key metabolite SAM as a bridge connecting the gluconeogenic enzyme PCK1 and H3K9 trimethylation in attenuating HCC progression, thus suggesting a potential therapeutic strategy against HCC.
Evidence on Effectiveness of Immune Checkpoint Inhibitors in Patients With Advanced Esophageal Squamous Cell Carcinoma
Authors: Zhen Gao, Sichao Wang, Shujie Huang
Journal: JAMA Oncology (2023)

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